Project 4: One-Carbon Metabolism, Oxidative Stress and As Toxicity

本项目涉及的超级基金项目生物医学研究的两个首要主题 涉及a）砷（As）的代谢和B）As诱导的氧化应激。存在显著的变异性 从砷暴露到疾病临床表现的进展。几项研究表明， 假设营养状况可以解释这种变异性很大一部分。无机As is 通过一碳代谢甲基化，这是一种依赖于叶酸的生物化学途径， 单碳基团。我们希望扩大我们的研究，这些研究已经开始描述 一碳代谢的营养调节对As甲基化的个体间变异性。 谷胱甘肽（GSH），主要抗氧化防御机制的关键组成部分，和电子供体 用于As还原的，由同型半胱氨酸合成，该合成受一碳的中间体调节， 新陈代谢.大量的基础研究，包括我们小组成员的突出工作， 指出，越来越多的人认为，作为消耗谷胱甘肽（GSH）和诱导氧化应激。但 砷暴露与氧化应激之间的关系尚未在人体中得到严格的研究 人口。 这项建议的第一个具体目标是利用由联合国建立的生物样品储存库， 队列研究（项目#2），进行巢式病例对照研究，以确定可改变的风险因素（例如： 氧化应激和/或高同型半胱氨酸血症）与对As诱导的皮肤损伤的易感性增加有关。 其余的具体目标将利用我们研究区域的扩展（以及Asfree的安装 威尔斯）招募375名目前暴露于砷的新成年人。在特定 目的2，我们将解决一个基本问题：在何种程度上尿砷代谢物反映砷 循环中的代谢物在具体目标3中，我们将进行一项横向研究，以测试 假设高浓度的s-腺苷高半胱氨酸（SAH）和低浓度的GSH 与As甲基化减少有关。在具体目标4中，我们建议检查剂量反应 砷暴露与氧化应激的关系。最后，我们将测试假设，减少 因为暴露会加重氧化应激。拟议的研究有可能a）证实， 在人群中诱导氧化应激并消耗GSH，B）连接As诱导的氧化应激和/或 营养状况与砷相关的临床结果，以及c）扩大我们对机制的理解 这些过程的基础。这些调查结果将对确定 潜在的有针对性的干预措施，以防止砷中毒。

Two overarching themes of the biomedical research of this Superfund Program addressed in this project relate to a) the metabolism of arsenic (As) and b) As-induced oxidative stress. There is significant variability in progression from As exposure to clinical manifestations of disease. Several studies have led to the hypothesis that nutritional status may account for a substantial portion of this variability. Inorganic As is methylated via one-carbon metabolism, a biochemical pathway that is dependent on folate for recruitment of one-carbon groups. We wish to expand our studies, which have begun to characterize the impact of nutritional regulation of one-carbon metabolism on the inter-individual variability in As methylation. Glutathione (GSH), a key component of the primary antioxidant defense mechanism, and the electron donor for As reduction, is synthesized from homocysteine, and this synthesis is regulated by intermediates of onecarbon metabolism. A great deal of basic research, including salient work from members of our group, points to the growing belief that As depletes glutathione (GSH) and induces oxidative stress. However, the relationship between As exposure and oxidative stress has not been rigorously examined in human populations. The first specific aim of this proposal will utilize the repository of biological samples established by the Cohort Study (Project #2) to conduct a nested case-control study to identify modifiable risk factors (e.g. oxidative stress and/or hyperhomocysteinemia) related to increased susceptibility to As-induced skin lesions. The remaining specific aims will take advantage of the expansion of our study area (and installation of Asfree tube wells) in Projects #3 and #7 to recruit 375 new adults who are currently exposed to As. In Specific Aim 2, we will address a fundamental question: To what extent do urinary As metabolites reflect As metabolites in the circulation? In Specific Aim 3, we will conduct a cross-sectional study to test the hypotheses that higher concentrations of s-adenosylhomocysteine (SAH) and lower concentrations of GSH are associated with reduced As methylation. In Specific Aim 4, we propose to examine dose-response relationships between As exposure and oxidative stress. Finally, we will test the hypothesis that reduction of As exposure alleviates oxidative stress. The proposed studies have the potential to a) substantiate that As induces oxidative stress and depletes GSH in a human population, b) link As-induced oxidative stress and/or nutritional status to an arsenic-related clinical outcome, and c) expand our understanding of the mechanisms underlying these processes. Such findings would have significant implications for the identification of potential targeted interventions for preventing As-toxicity.